U.S. patent application number 13/207656 was filed with the patent office on 2013-02-14 for controlling moisture in and plasticization of bioresorbable polymer for melt processing.
This patent application is currently assigned to Abbott Cardiovascular Systems Inc.. The applicant listed for this patent is Ni Ding, Manish Gada, Thierry Glauser, Lothar W. Kleiner, James P. Oberhauser, Stephen D. Pacetti, Bethany Steichen, Yunbing Wang. Invention is credited to Ni Ding, Manish Gada, Thierry Glauser, Lothar W. Kleiner, James P. Oberhauser, Stephen D. Pacetti, Bethany Steichen, Yunbing Wang.
Application Number | 20130041129 13/207656 |
Document ID | / |
Family ID | 46924520 |
Filed Date | 2013-02-14 |
United States Patent
Application |
20130041129 |
Kind Code |
A1 |
Steichen; Bethany ; et
al. |
February 14, 2013 |
Controlling Moisture In And Plasticization Of Bioresorbable Polymer
For Melt Processing
Abstract
Methods and systems for controlling the moisture content of
biodegradable and bioresorbable polymer resin during extrusion
above a lower limit that allows for plasticization of the polymer
resin melt and below an upper limit to reduce or prevent molecular
weight loss are disclosed. Methods are further disclosed involving
plasticization of a polymer resin for feeding into an extruder with
carbon dioxide and freon.
Inventors: |
Steichen; Bethany; (San
Francisco, CA) ; Pacetti; Stephen D.; (San Jose,
CA) ; Gada; Manish; (Santa Clara, CA) ;
Glauser; Thierry; (Redwood City, CA) ; Kleiner;
Lothar W.; (Los Altos, CA) ; Wang; Yunbing;
(Sunnyvale, CA) ; Oberhauser; James P.; (Saratoga,
CA) ; Ding; Ni; (San Jose, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Steichen; Bethany
Pacetti; Stephen D.
Gada; Manish
Glauser; Thierry
Kleiner; Lothar W.
Wang; Yunbing
Oberhauser; James P.
Ding; Ni |
San Francisco
San Jose
Santa Clara
Redwood City
Los Altos
Sunnyvale
Saratoga
San Jose |
CA
CA
CA
CA
CA
CA
CA
CA |
US
US
US
US
US
US
US
US |
|
|
Assignee: |
Abbott Cardiovascular Systems
Inc.
Santa Clara
CA
|
Family ID: |
46924520 |
Appl. No.: |
13/207656 |
Filed: |
August 11, 2011 |
Current U.S.
Class: |
528/354 ;
422/105 |
Current CPC
Class: |
B29C 48/277 20190201;
B29C 2948/92695 20190201; B29B 13/06 20130101; B29B 13/065
20130101; B29C 48/267 20190201; B29K 2995/006 20130101; B29C
2948/92228 20190201; B29C 48/295 20190201; B29C 48/288 20190201;
B29C 48/05 20190201; B29C 48/09 20190201; B29C 2948/92342 20190201;
B29C 48/08 20190201; Y02P 70/10 20151101; B29C 48/287 20190201;
B29C 48/92 20190201; B29C 48/143 20190201; B29C 48/0022 20190201;
B29C 2948/922 20190201; B29C 48/276 20190201; B29C 2948/92723
20190201; B29C 2948/92704 20190201; B29C 2948/92333 20190201; B29C
48/76 20190201 |
Class at
Publication: |
528/354 ;
422/105 |
International
Class: |
A61L 31/06 20060101
A61L031/06; C08G 63/90 20060101 C08G063/90; G05B 1/00 20060101
G05B001/00 |
Claims
1. A method comprising: providing a bioresorbable polymer resin as
feed to an extruder for an extrusion process; passing a drying gas
through the polymer resin during the extrusion process prior to
being fed into the extruder to remove moisture from the polymer
resin, wherein the drying gas has substantially no moisture content
prior to passing through the polymer resin; maintaining the
moisture content of the polymer resin during the extrusion process
prior to being fed into the extruder in a selected range between 50
ppm and 1000 ppm; and adjusting the temperature of the drying gas,
the flow rate of the drying gas, or both to maintain the moisture
content of the polymer resin in the selected range.
2. The method of claim 1, wherein the drying gas has a dew point of
less than -40 deg C.
3. The method of claim 1, further comprising passing the drying gas
through the polymer resin prior to starting the extrusion process,
wherein the moisture content of the polymer resin is reduced to
between 100 and 1000 ppm prior to starting the extrusion
process.
4. The method of claim 1, further comprising monitoring the
moisture content of the drying gas and adjusting the temperature of
the drying gas or adjusting the flow rate of the drying gas or both
based on the monitored moisture content.
5. The method of claim 1, further comprising measuring the moisture
content of the polymer resin and adjusting the temperature of the
drying gas or adjusting the flow rate of the drying gas or both
based on the measured moisture content of the polymer resin.
6. The method of claim 1, wherein the polymer resin is in a sealed
container that reduces or minimizes leakage of ambient moisture
into the container.
7. The method of claim 1, wherein the temperature of the drying gas
is initially 40 to 70 deg C. and is adjusted to 25 to 30 deg C.
after the moisture content of the polymer resin is reduced to
between 50 and 100 ppm.
8. The method of claim 1, wherein the bioresorbable polymer has an
inherent viscosity of at least 2 dl/gm.
9. The method of claim 1, where the bioresorbable polymer is
selected from the group consisting of poly(L-lactide) (PLLA),
poly(D-lactide) (PDLA), polyglycolide (PGA),
Poly(L-lactide-co-D,L-lactide) (PLDLA), poly(D,L-lactide) (PDLLA),
poly(D,L-lactide-co-glycolide) (PLGA) and
poly(L-lactide-co-glycolide) (PLLGA).
10. A method comprising providing a bioresorbable polymer resin as
feed to an extruder for an extrusion process; controlling the
moisture content of the polymer resin during the extrusion process
prior to feeding to the extruder to be within a selected range
between 50 ppm and 1000 ppm; and adjusting the moisture content of
a drying gas stream passing through the polymer resin to control
the moisture content of the polymer resin.
11. The method of claim 10, further comprising passing the drying
gas through the polymer resin prior to starting the extrusion
process, wherein the moisture content of the polymer resin is
reduced to less than 1000 ppm prior to adjusting the moisture
content of the drying gas stream.
12. The method of claim 10, wherein the moisture content of the
drying gas stream is adjusted based on moisture content of the
drying gas stream measured before passing through the polymer
resin, after passing through the polymer resin, or both.
13. The method of claim 10, wherein the moisture content of the
drying gas stream is adjusted to control the moisture content of
the drying gas stream to be within a selected range of drying gas
moisture content which corresponds to the selected range of
moisture content of the polymer resin.
14. The method of claim 10, wherein the moisture content of the
drying gas stream is adjusted to control the moisture content of
the drying gas stream to be within a specified tolerance of a
target moisture content, wherein the target moisture content of the
drying gas stream corresponds to a target value of moisture content
of the polymer resin within the selected range of the polymer resin
moisture content.
15. The method of claim 10, wherein adjustment of the moisture
content of the drying gas includes increasing or decreasing the
moisture content of the drying gas stream in order to maintain the
polymer resin moisture content within the selected range.
16. The method of claim 10, wherein the drying gas stream includes
a dry gas stream, wherein the moisture content of the drying gas
stream is adjusted through variation of injection of a moist gas
stream into the dry gas stream.
17. The method of claim 16, wherein the drying gas has a dew point
of less than -40 deg C.
18. The method of claim 10, wherein the polymer resin is in a
sealed container that minimizes leakage of ambient moisture into
the container.
19. A system comprising: a resin hopper drier for holding polymer
resin having an outlet port for connecting to an extruder for
feeding the polymer resin through the outlet port to the extruder;
a source of a dry gas stream and conduits for carrying the dry gas
stream from the dry gas stream source; a source of a moist gas
stream and a conduit for carrying the moist gas stream from the
moist gas stream source, wherein the conduit from the moist gas
stream source is configured to inject the moist gas stream into the
dry gas stream to form a drying gas stream; a conduit for carrying
the drying gas stream into a gas inlet port to the resin hopper; a
conduit for carrying the drying gas stream from a gas outlet port
from the resin hopper; a sensor to monitor moisture content of the
drying gas; and a controller that generates a signal to adjust the
moisture content of the drying gas based on the monitored moisture
content of the drying gas.
20. A method comprising providing a biodegradable polymer resin as
feed to an extruder for an extrusion process; and passing a gas
containing carbon dioxide through the polymer resin prior to
entering the extruder during the extrusion process, wherein the
polymer resin absorbs some of the carbon dioxide which reduces melt
viscosity of the polymer resin in the extruder during the extrusion
process.
21. The method of claim 20, wherein the carbon dioxide is in a
supercritical state.
22. The method of claim 20, wherein the gas is 10 to 50 vol %
carbon dioxide prior to entering the hopper.
23. A method comprising: providing a biodegradable polymer resin as
feed to an extruder for an extrusion process; and passing a gas
containing freon through the polymer resin prior to entering the
extruder during the extrusion process, wherein the polymer resin
absorbs some of the freon which reduces melt viscosity of the
polymer resin in the extruder during the extrusion process.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention relates to methods of manufacturing polymeric
medical devices, in particular, stents.
[0003] 2. Description of the State of the Art
[0004] This invention relates to manufacturing of biodegradable and
bioresorbable medical devices. These devices include, but are not
limited to radially expandable endoprostheses, that are adapted to
be implanted in a bodily lumen. An "endoprosthesis" corresponds to
an artificial device that is placed inside the body. A "lumen"
refers to a cavity of a tubular organ such as a blood vessel. A
stent is an example of such an endoprosthesis. Stents are generally
cylindrically shaped devices that function to hold open and
sometimes expand a segment of a blood vessel or other anatomical
lumen such as urinary tracts and bile ducts. Stents are often used
in the treatment of atherosclerotic stenosis in blood vessels.
"Stenosis" refers to a narrowing or constriction of a bodily
passage or orifice. In such treatments, stents dilate stenotic
regions, hold dissections in place, and prevent vasospasm and
abrupt closure following angioplasty in the vascular system. A
complication following stenting or balloon angioplasty is
restenosis. "Restenosis" refers to the reoccurrence of stenosis in
a blood vessel or heart valve after it has been treated (as by
balloon angioplasty, stenting, or valvuloplasty) with apparent
success.
[0005] Stents are typically composed of scaffolding that includes a
pattern or network of interconnecting structural elements or
struts, formed from wires, tubes, or sheets of material rolled into
a cylindrical shape. This scaffolding gets its name because it
physically holds open and, if desired, expands the wall of the
passageway. Typically, stents are capable of being compressed or
crimped onto a catheter so that they can be delivered to and
deployed at a treatment site.
[0006] Delivery includes inserting the stent through small lumens
using a catheter and transporting it to the treatment site.
Deployment includes expanding the stent to a larger diameter once
it is at the desired location. Mechanical intervention with stents
has reduced the rate of restenosis as compared to balloon
angioplasty.
[0007] Stents are used not only for mechanical intervention but
also as vehicles for providing biological therapy. Medicated stents
provides biological therapy through local administration of a
therapeutic substance. A medicated stent may be fabricated by
coating the surface of either a metallic or polymeric scaffolding
with a polymeric carrier that includes an active or bioactive agent
or drug. A polymeric scaffolding may also serve as a carrier of an
active agent or drug.
[0008] A biodegradable stent must be able to satisfy a number of
mechanical requirements. The stent must be capable of withstanding
the structural loads, namely radial compressive forces, imposed on
the stent as it supports the walls of a vessel. Therefore, a stent
must possess adequate radial strength. Radial strength, which is
the ability of a stent to resist radial compressive forces, relates
to a stent's radial yield strength and radial stiffness around a
circumferential direction of the stent. A stent's "radial yield
strength" or "radial strength" (for purposes of this application)
may be understood as the compressive loading, which if exceeded,
creates a yield stress condition resulting in the stent diameter
not returning to its unloaded diameter, i.e., there is
irrecoverable deformation of the stent. When the radial yield
strength is exceeded the stent is expected to yield more severely
and only a minimal force is required to cause major
deformation.
[0009] A biodegradable stent may be designed to fulfill it clinical
purpose and then be resorbed. Once expanded, such a stent should
adequately maintain its size and shape for a period of time to
maintain patency or provide structural tissue support of a blood
vessel despite the various forces that may come to bear on it,
including the cyclic loading induced by the beating heart. In an
exemplary treatment, a stent provides patency to a lumen for a
period of time, its mechanical properties decline, it loses
structural integrity, and then it is resorbed.
[0010] However, there are several challenges in making a
bioabsorbable polymeric stent that provides desirable treatment
outcomes. The mechanical and degradation behavior of a
biodegradable stent, and the potential clinical outcomes, are quite
sensitive to the properties of the biodegradable polymer of a
finished product. These challenges include developing manufacturing
methods that provide properties of the finished product that
provide the desirable treatment outcomes.
INCORPORATION BY REFERENCE
[0011] All publications and patent applications mentioned in this
specification are herein incorporated by reference to the same
extent as if each individual publication or patent application was
specifically and individually indicated to be incorporated by
reference, and as if each said individual publication or patent
application was fully set forth, including any figures, herein.
SUMMARY OF THE INVENTION
[0012] Various embodiments of the present invention include a
method comprising: providing a biodegradable or bioresorbable
polymer resin as feed to an extruder for an extrusion process;
passing a drying gas through the polymer resin during the extrusion
process prior to being fed into the extruder to remove moisture
from the polymer resin, wherein the drying gas has substantially no
moisture content prior to passing through the polymer resin;
maintaining the moisture content of the polymer resin during the
extrusion process prior to being fed into the extruder in a
selected range between 50 ppm and 1000 ppm; and adjusting the
temperature of the drying gas, the flow rate of the drying gas, or
both to maintain the moisture content of the polymer resin in the
selected range.
[0013] Further embodiments of the present invention a method
comprising: providing a biodegradable polymer resin as feed to an
extruder for an extrusion process; controlling the moisture content
of the polymer resin during the extrusion process prior to feeding
to the extruder to be within a selected range between 50 ppm and
1000 ppm; and adjusting the moisture content of a drying gas stream
passing through the polymer resin to control the moisture content
of the polymer resin.
[0014] Additional embodiments of the present invention include a
system comprising: a resin hopper for holding polymer resin having
an outlet port for connecting to an extruder for feeding the
polymer resin through the outlet port to the extruder; a source of
a dry gas stream and conduits for carrying the dry gas stream from
the dry gas stream source; a source of a moist gas stream and a
conduit for carrying the moist gas stream from the moist gas stream
source, wherein the conduit from the moist gas stream source is
configured to inject the moist gas stream into the dry gas stream
to form a drying gas stream; a conduit for carrying the drying gas
stream into a gas inlet port to the resin hopper; a conduit for
carrying the drying gas stream from a gas outlet port from the
resin hopper; a sensor to monitor moisture content of the drying
gas; and a controller that generates a signal to adjust the
moisture content of the drying gas based on the monitored moisture
content of the drying gas.
[0015] Other embodiments of the present invention include a method
comprising: providing a biodegradable polymer resin as feed to an
extruder for an extrusion process; and passing a gas containing dry
carbon dioxide through the polymer resin prior to entering the
extruder during the extrusion process, wherein the polymer resin
absorbs some of the carbon dioxide which reduces melt viscosity of
the polymer resin in the extruder during the extrusion process,
wherein the gas may also reduce the moisture content of the polymer
resin prior to entering the extruder.
[0016] Additional embodiments of the present invention include a
method comprising: providing a biodegradable polymer resin as feed
to an extruder for an extrusion process; and passing a gas
containing freon or one of its replacement gases currently on the
market through the polymer resin prior to entering the extruder
during the extrusion process, wherein the polymer resin absorbs
some of the freon which reduces melt viscosity of the polymer resin
in the extruder during the extrusion process, wherein the gas may
also reduce the moisture content of the polymer resin prior to
entering the extruder.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] FIG. 1 depicts a stent.
[0018] FIG. 2 depicts the effect of monomer content on a PLLA
scaffold degradation rate constant, k, from in vitro studies.
[0019] FIG. 3 depicts a schematic representation of an exemplary
system for controlling moisture content of a polymer resin prior to
and during extrusion.
[0020] FIG. 4 depicts a schematic representation of an exemplary
system for controlling moisture content of a polymer resin prior to
and during extrusion with a drying gas having variable moisture
content.
[0021] FIG. 5 depicts a schematic representation of another
exemplary system for controlling moisture content of a polymer
resin prior to and during extrusion with a drying gas having
variable moisture content.
DETAILED DESCRIPTION OF THE INVENTION
[0022] Various embodiments of the present invention relate to
manufacture of polymeric implantable medical devices. In
particular, the embodiments include methods of conditioning
biodegradable polymer resin for melt processing. Such melt
processing methods may be used to form polymer constructs from the
conditioned resin that are subsequently processed to form
implantable medical devices. Alternatively, such melt processing
methods may form implantable medical devices directly from the
resin. Melting processing methods can include, but are not limited
to, extrusion, injection molding, injection blow molding,
compression molding, or batch melt processing.
[0023] The methods described herein are generally applicable to any
amorphous or semi-crystalline polymeric implantable medical device,
especially those that have load bearing portions when in use or
have portions that undergo deformation during use. In particular,
the methods can be applied to tubular implantable medical devices
such as self-expandable stents, balloon-expandable stents, and
stent-grafts.
[0024] A stent may include a pattern or network of interconnecting
structural elements or struts. FIG. 1 depicts a view of a stent
100. In some embodiments, a stent may include a body, backbone, or
scaffolding having a pattern or network of interconnecting
structural elements 105. Stent 100 may be formed from a tube (not
shown). The structural pattern of the device can be of virtually
any design. The embodiments disclosed herein are not limited to
stents or to the stent pattern illustrated in FIG. 1. The
embodiments are easily applicable to other patterns and other
devices. The variations in the structure of patterns are virtually
unlimited.
[0025] A stent such as stent 100 may be fabricated from a polymeric
tube or a sheet by rolling and bonding the sheet to form the tube.
A tube or sheet can be formed by extrusion or injection molding. A
stent pattern, such as the one pictured in FIG. 1, can be formed in
a tube or sheet with a technique such as laser cutting or chemical
etching. The stent can then be crimped on to a balloon or catheter
for delivery into a bodily lumen.
[0026] An implantable medical device of the present invention can
be made partially or completely from a biodegradable,
bioresorbable, bioabsorbable, or biostable polymer. A polymer for
use in fabricating an implantable medical device can be biostable,
bioresorbable, bioabsorbable, biodegradable or bioerodable.
Biostable refers to polymers that are not biodegradable. The terms
biodegradable, bioresorbable, bioabsorbable, and bioerodable are
used interchangeably and refer to polymers that are capable of
being completely degraded and/or eroded into different degrees of
molecular levels when exposed to bodily fluids such as blood and
can be gradually resorbed, absorbed, and/or eliminated by the body.
The processes of breaking down and absorption of the polymer can be
caused by, for example, hydrolysis and metabolic processes.
[0027] A stent made from a biodegradable polymer is intended to
remain in the body for a duration of time until its intended
function of, for example, maintaining vascular patency and/or drug
delivery is accomplished. After the process of degradation,
erosion, absorption, and/or resorption has been completed, no
portion of the biodegradable stent, or a biodegradable portion of
the stent will remain. In some embodiments, very negligible traces
or residue may be left behind.
[0028] The duration of a treatment period depends on the bodily
disorder that is being treated. In treatments of coronary heart
disease involving use of stents in diseased vessels, the duration
can be in a range from several months to a few years. The duration
is typically up to about six months, twelve months, eighteen
months, or two years. In some situations, the treatment period can
extend beyond two years.
[0029] A stent has certain mechanical requirements such as high
radial strength, high stiffness or high modulus, and high fracture
toughness. A stent that meets such requirements greatly facilitates
the delivery, deployment, and treatment of a diseased vessel. With
respect to radial strength and stiffness, a stent must have
sufficient radial strength to withstand structural loads, namely
radial compressive forces, imposed on the stent so that the stent
can support the walls of a vessel at a selected diameter for a
desired time period. A polymeric stent with inadequate radial
strength and/or stiffness can result in an inability to maintain a
lumen at a desired diameter for a sufficient period of time after
implantation into a vessel. In vessels which undergo a great deal
of movement, such as those of the extremities, the polymeric stent
must be able to accommodate these deformations and return to its
original shape. This reversibility requires a higher degree of
elasticity and crush resistance than that needed for stenting a
coronary vessel.
[0030] In addition, the stent should possess sufficient toughness
or resistance to fracture to allow for crimping, expansion, and
cyclic loading. These aspects of the use of the stent involve
deformation of various portions of the stent. Sufficient toughness
is important to prevent cracking or fracture during use which could
lead to premature mechanical failure of the stent.
[0031] The strength deficiency of polymers compared to metals may
be addressed by incorporating a deformation step in the stent
fabrication process by subjecting the polymer construct to
deformation. Deforming polymers tends to increase the strength
along the direction of deformation, which is believed to be due to
the induced polymer chain orientation along the direction of
deformation.
[0032] Semi-crystalline polymers that are stiff or rigid under
biological conditions or conditions within a human body are
particularly suitable for use as a scaffolding material.
Specifically, polymers that have a glass transition temperature
(Tg) sufficiently above human body temperature which is
approximately 37.degree. C., should be rigid upon implantation.
Poly(L-lactide) (PLLA) is an example of such a polymer.
[0033] Additional exemplary biodegradable polymers for use with a
bioabsorbable polymer scaffolding include poly(D-lactide) (PDLA),
polyglycolide (PGA), poly(L-lactide-co-D,L-lactide) (PLDLA),
poly(D,L-lactide) (PDLLA), poly(D,L-lactide-co-glycolide) (PLGA)
and poly(L-lactide-co-glycolide) (PLLGA). With respect to PLLGA,
the stent scaffolding can be made from PLLGA with a mole % of GA
between 5-15 mol %. The PLLGA can have a mole % of (LA:GA) of 85:15
(or a range of 82:18 to 88:12), 95:5 (or a range of 93:7 to 97:3),
or commercially available PLLGA products identified as being 85:15
or 95:5 PLLGA. The examples provided above are not the only
polymers that may be used. Many other examples can be provided,
such as those found in Polymeric Biomaterials, second edition,
edited by Severian Dumitriu; chapter 4.
[0034] Detailed discussion of the manufacturing process of a
bioabsorbable stent can be found elsewhere, e.g., U.S. Patent
Publication No. 20070283552. The fabrication methods of a
bioabsorbable stent can include the following steps:.
[0035] (1) forming a polymeric tube from a biodegradable polymer
resin using extrusion,
[0036] (2) radially deforming the formed tube to increase radial
strength,
[0037] (3) forming a stent scaffolding from the deformed tube by
laser machining a stent pattern in the deformed tube with laser
cutting, in exemplary embodiments, the strut thickness can be
100-200 microns, or more narrowly, 120-180, 130-170, or 140-160
microns,
[0038] (4) optionally forming a therapeutic coating over the
scaffolding,
[0039] (5) crimping the stent over a delivery balloon, and
[0040] (6) sterilization with election-beam (E-beam) radiation.
[0041] With respect to step (1), an extruder generally includes a
barrel through which a polymer melt is conveyed from an entrance to
an exit port. The polymer resin is typically fed into an extruder
from a container called hopper. The hopper can be unsealed and
allow exposure of the resin to the ambient air, or alternatively,
it can be sealed to minimize prevent such exposure. The resin is
feed to the extruder barrel near its proximal end from the hopper
as a solid, for example, in the form of a pellet or granule. The
solid polymer is melted as it is conveyed through the barrel and
mixed, for example, through interaction with rotating screws. The
polymer in the extruder barrel is heated to temperatures above the
melting temperature (Tm) of the polymer and exposed to pressures
that are generally far above ambient. Since the viscosity and
temperature are inversely related for a polymer, the extrusion
temperature is raised to a level that allows a desired flow rate of
polymer through the extruder.
[0042] The processing parameters of some or all manufacturing steps
are crucial to providing a finished stent product that provides
mechanical properties and degradation properties important for a
desired clinical outcome. Degradation properties include both the
time dependence of mechanical properties and the biodegradation or
bioresorption rate, e.g., time for complete resorption. The
inventors have found properties and clinical behavior of the
finished stent product are quite sensitive to certain processing
parameters. In particular, studies by inventors have shown that the
degradation profile of poly(L-lactide) is strongly dependent on
number average molecular weight (Mn) of the finished stent product
and the degradation rate constant of PLLA, U.S. patent application
Ser. No. 13/104,732. In systematic studies, the inventors have
found that the degradation rate constant of PLLA is strongly
dependent on the L-lactide (LLA) monomer content. FIG. 2 depicts
the effect of LLA monomer content on a PLLA scaffold degradation
rate constant, k, from in vitro studies. Therefore, the hydrolytic
degradation of a PLLA scaffold has been shown to increase with an
increase in LLA monomer content. As a result, the Mn and radial
strength as a function of time also depend on LLA monomer content.
In vitro bioresorption studies of PLLA scaffolds with different LLA
monomer concentrations demonstrated that Mn degrades faster as the
LLA monomer content increases. These studies also demonstrated that
as the LLA monomer content increases the radial strength of the
scaffold is maintained for a shorter period of time.
[0043] It has further been found that the processing steps that
cause the most significant decrease in molecular weight of PLLA are
extrusion (or more generally, melt processing) and e-beam
sterilization. Additionally, it has been found that the principal
source of LLA monomer generation is the extrusion step. Both the
drop in molecular weight and monomer generation increases with
extrusion temperature.
[0044] Thus, extrusion of a biodegradable polymer resin, such as
PLLA resin, into tubing for stent fabrication is a critical
manufacturing step since stent properties (Mn and L-lactide monomer
content) important in clinical behavior depend on extrusion
parameters. The extrusion step is a challenge both because of the
resin properties and the many tubing requirements which must be
met.
[0045] One challenge is that the high molecular weight PLLA (e.g.,
Mn of 260 to 370 kDa) resin used has a high inherent viscosity
(3.3-4.3 dl/g). The inherent viscosity (of a polymer) is the ratio
of the natural logarithm of the relative viscosity, .theta..sub.r,
to the mass concentration of the polymer, c, i.e.,
.theta..sub.inh=ln(.theta..sub.r/c). High temperatures and
pressures are required to extrude, or generally, to melt process
such a resin. For example, parameters include an extrusion
temperature between 210 and 260 deg C., an extruder barrel pressure
of about 2000 psi, and a residence time of about 10 min. It is
believed that the high temperature, high shear, and long residence
time causes thermally-induced chain scission that results in a
large drop in molecular weight, for example, from a pre-extrusion
Mn of 265 kDa to a post-extrusion Mn of 180 kDa.
[0046] A lower IV or molecular weight resin would be much easier to
process (lower temperature, pressure, shear), but the final Mn of
the finished stent product may be too low for a desired clinical
outcome due to the drop in Mn from both extrusion and
sterilization. The magnitude of the radial strength and the time
that radial strength is maintained decrease as the Mn of the
finished stent product decreases. The Mn of the finished product
must be high enough so that the radial strength is high enough to
support a vessel and will be maintained for a sufficient time.
[0047] Additionally, the inventors have found in processing PLLA
that a melt processing temperature that is too high leads to
excessive monomer generation as well as oligomers, all of which
affect subsequent degradation time of a finished good implanted in
a patient. It is believed that monomer generation is caused by a
transesterification reaction (end group back biting). This
depolymerization reaction is caused by a combination of exceeding a
critical temperature and residence time during extrusion, which
causes this additional degradation mechanism. An increased
degradation rate decreases the time to complete absorption and also
shortens the time that radial strength is maintained. Thus, there
is an upper limit to the monomer content for satisfactory stent
performance. For LLA monomer in PLLA, LLA may generally be less
than 1 wt %. As indicated above, higher temperatures and melt
residence times during extrusion to process the high IV resin
increases monomer content.
[0048] Other challenges include that (1) a small variation in IV
leads to significant process changes, since viscosity is
proportional to (IV).sup.5; (2) strict specifications must be met
for the tubing dimensions of ID, OD, concentricity, and ovality;
and (3) gel counts must be low, which requires a dense screen pack.
This leads to high operating pressures and additional localized
shear heating.
[0049] Another significant challenge in extrusion is addressing
moisture content of the biodegradable polymer resin. Studies by
inventors indicated that the moisture level in PLLA resin was a
critical parameter for control of both molecular weight and monomer
content during extrusion. The inventors have recognized that both
too much moisture and too little moisture in the resin during
extrusion can have an undesirable impact of the properties of the
extruded construct and in the final stent product.
[0050] The inventors have found that when the moisture level of the
resin was too high (e.g., greater than 1000 ppm), molecular weight
degradation or loss of the resin IV increased. It is believed that
the increased molecular weight loss arises from chain scission due
to more hydrolysis at the high processing temperature. This
was,observed even if the extrusion was done at a temperature as low
as 210 deg C. (410 deg F.).
[0051] It was found from studies that when the moisture content was
too low (e.g., lower than 50 ppm), the melt viscosity of the PLLA
resin in the extruder increased. As a result the processing
temperature in the extruder was increased to maintain product
quality and consistency (e.g., maintain transparency of extruded
product), for example, the temperature was increased to 238 deg C.
(460 deg F.) and above. It is believed that moisture content in a
polymer resin melt acts as a significant plasticizer which
decreases melt viscosity. Thus, it is believed the increased melt
viscosity at the low moisture content was due to loss of or
decrease in the degree of the plasticizing effect. An increase in
molecular weight loss and monomer generation was observed in tubes
extruded at the higher temperatures from the low moisture content
resin. It is believed that these effects are caused at least in
part to the increase in reactions that reduce molecular weight and
generate monomer.
[0052] A conventional method of reducing moisture content in PLLA
resin was implemented by the inventors. In this method, the PLLA
resin was dried in a vacuum oven to a very low level, less than 5
ppm. For example, the resin was baked in a vacuum oven at about 60
deg C. for 6 hours and then at about 120 deg C. for about 6 hours.
The dried resin was then transferred to an open hopper of the
extruder several times during the extrusion process. It was found
that once the dried resin was transferred to the open hopper, its
moisture level increased during extrusion. Product consistency was
found to be inconsistent. Specifically, the monomer content of the
tubes extruded during extrusion runs was found to vary. As time
progressed, the monomer content of the tubes was found to decrease.
It is believed that the moisture content of resin entering the
extruder increased with time since the resin with the longer
residence time in the open hopper absorbed moisture from the
environment in the facility. It is hypothesized that the low
moisture content resin with the shorter residence time in the
hopper entering at the start of the extrusion run had a higher melt
viscosity which mechanical degradation due to shear which can
result in random chain scission.
[0053] Therefore, to summarize, too high of a moisture content
results in increased molecular weight loss and too low of moisture
content results in increased monomer generation and molecular
weight loss. High moisture content causes hydrolytic degradation,
which is random. Monomer content is increased when a critical
temperature (approximately 220 to 240 deg C.) and critical
residence time are exceeded (approximately 13 minutes). There are
three degradation mechanisms in play simultaneously: (1) mechanical
degradation due to shear which causes random chain scission; (2)
hydrolytic degradation which also causes chain scission; and (3)
monomer generation which essentially is de.sub.polymerization. All
three occur at the same time and the extent of each depends upon
the complexity of shear, temperature, residence time, and moisture
content.
[0054] Thus, based on the above studies, it was found that methods
were needed to control the moisture content of polymer resin during
extrusion above a lower limit that allows for plasticization of the
polymer resin melt and below an upper limit to reduce molecular
weight loss observed at higher moisture content. The upper moisture
limit is low enough so as not to result any or significant
hydrolytic degradation. Additionally, methods are needed to
plasticize the biodegradable resin to a consistent level with water
or other agents. Consistent plasticization of the PLLA resin during
extrusion facilitates achieving both uniform and consistent
extruded product, e.g., tube appearance, molecular weight, monomer
content, and other properties. Exemplary lower limits can include
50, 100, 150, 200, 250, 300, 350, and 400 ppm. Exemplary upper
limits include 100, 200, 300, 500, 700, 1000, 2000, and 3000 ppm.
Exemplary ranges include any combination of the above lower limits
with any of the upper limits that is higher. An exemplary preferred
range may be 50 to 1000 ppm. When the extrusion temperature (molten
PLLA) is lower, the moisture content can be higher.
[0055] Certain embodiments of controlling moisture in a polymer
resin for extrusion include placing the polymer resin in a
container with an outlet for feeding to the resin to the extruder.
The container may be referred to as a hopper drier. The resin may
be fed directly from the container into the extruder. The container
is sealable to minimize or prevent exposure of the polymer resin to
ambient moisture, i.e., ambient air that has a moisture content
depending upon relative humidity. In certain practical
implementations, there is leakage of ambient moisture into the
sealed container prior to and during extrusion to maintain a low,
but stable or constant moisture level in the PLLA. Prior to
starting extrusion, the resin in the sealed container may be dried
by circulating a drying gas through the resin to reduce the
moisture content of the polymer resin to a very low level. For
example, the resin may be dried to a moisture content between 50
and 1000 ppm, or more narrowly, 100 to 500 ppm, or 100 to 300 ppm.
The drying time may be, for example, 1 to 6 hours, or more,
narrowly 4 to 6 hours, or greater than 6 hours.
[0056] The drying gas may be a low moisture content gas such as air
or nitrogen. The drying gas may be supplied by a source such as a
compressed gas tank. After passing the dry gas stream through the
resin, the gas stream may be passed through a desiccant bed to
remove moisture from the gas absorbed from the resin. The gas may
then be recycled to the resin. Exemplary equipment for drying a
polymer resin in a hopper is a Dri-Air desiccant dryer from Dri-Air
Industries, Inc. of East Windsor, Conn. The drying gas passed
through the resin may be free or substantially free of moisture.
For example, the drying gas may be air with a dew point of less
than -40 or -45 deg C. A moisture sensor can monitor the moisture
content (e.g., dew point temperature, relative humidity) of the
drying gas prior to circulating the drying gas through the resin.
The temperature of the drying process may correspond to the
temperature of the drying gas or the temperature inside the
container. The drying temperature may be 25 to 70 deg C., or more
narrowly, 25 to 30 deg C., 30 to 40 deg C., 40 to 50 deg C., 50 to
60 deg C., or 60 to 70 deg C. Temperature sensors can monitor the
temperature of the drying gas prior to passing through the
container and the temperature inside the container. The flow rate
of drying gas may be 5 to 15 m.sup.3/hr at the drying temperature.
During extrusion, the drying gas circulation through the resin may
be maintained. A higher temperature may be preferred since the rate
of removal of the moisture from the resin is faster at higher
temperatures. Therefore, the drying time required to reach a
selected range of moisture content decreases with increasing
temperature.
[0057] In some embodiments, the moisture level of the resin may be
controlled to be in a selected range during extrusion. Maintaining
the pre-extrusion drying conditions may cause the moisture content
of the resin to continue to decrease. Therefore, since the drying
is free or substantially free of moisture, continued circulation of
the drying gas may reduce the moisture content of the resin below a
desired lower limit.
[0058] The moisture level of the drying gas inside the container or
after exiting the container may be monitored by moisture sensors
that measure the relative humidity or the ppm of moisture. High
precision humidity sensors are available from Vaisala of San Jose,
Calif. Alternatively, a sample of resin may be removed from the
container and the moisture content of the resin determined. The
drying temperature, the flow rate of drying gas, or both may be
adjusted to maintain the moisture content of the resin in a desired
range, in particular, above the lower limit.
[0059] In certain embodiments, the temperature of the drying gas or
container may be decreased to control the moisture content of the
resin. In exemplary embodiments, the temperature may be decreased
from 60 to 70 deg C. to 25 to 30 deg C., or more generally,
decreased by 5, 10, 15, 20, 30, 35, or 40 deg C. In exemplary
embodiments, the flow rate can be decreased to maintain the
moisture content of the resin above the lower limit. The flow rate
can be decreased to 75 to 95%, 50 to 75%, 25 to 50%, 10 to 25%, or
less than 10% of the initial flow rate. In some embodiments, the
flow rate of the drying gas may be stopped for a period of time
after the start of extrusion.
[0060] The moisture content can be monitored periodically after
such adjustment(s). If the moisture content rises above an upper
limit after such adjustments, the temperature, flow rate of drying
gas, or both can be adjusted to maintain the moisture content of
the resin below the upper limit. In exemplary embodiments, the
temperature may increased by 5, 10, 15, 20, 30, 35, or 40 deg C. In
exemplary embodiments, the flow rate of the drying gas can be
increased to maintain the moisture content of the resin below the
upper limit. The flow rate may be increased to 75 to 100%, 50 to
75%, 25 to 50%, or 10 to 25% of the initial flow rate. In some
embodiment, the flow rate can be restarted after having been turned
off and returned to an initial level, a higher level, or lower
level.
[0061] FIG. 3 depicts a schematic representation of an exemplary
system 120 for controlling moisture content of a polymer resin
prior to and during extrusion. System 120 includes a resin hopper
122 that holds resin that is fed to an extruder (not shown) as
shown by an arrow 124. A drying gas stream 128 enters hopper 122
and passes through the resin in the hopper. The temperature and
humidity of drying gas 128 is monitored prior to entering hopper
122 by temperature and humidity sensors 130. A drying gas stream
129 exits hopper 122 after having passed through and removed
moisture from the resin. A humidity sensor 133 monitors the
humidity of drying gas stream 129. A pressure sensor 131 monitors
the pressure of drying gas stream 128. Drying gas stream 129 is
directed to a dryer unit 126, such as a desiccant bed, to remove
moisture from the drying gas absorbed from the polymer resin.
System 120 can include two desiccant beds (not shown). Drying gas
may be directed through one bed while the other is regenerated
(moisture is removed). An overpressure valve 134 releases excess
pressure from the system. Dryer unit 126 removes moisture from
drying gas stream 129 to generate drying gas stream 128 that is
free or substantially free of moisture. The temperature of the
drying gas can be adjusted by a heat exchanger (not shown) to
control the moisture content of the resin. The flow rate of the
drying gas can be increased or decreased by a flow rate controller
(not shown).
[0062] Further embodiments of the present invention include
controlling the moisture content of a polymer resin during
extrusion to be within a selected range or to be within a specified
tolerance of a target value by adjusting the moisture content of a
drying gas stream passing through the polymer resin. The selected
range may be between a lower limit and upper limit, as disclosed
above. In such embodiments, the polymer resin may be contained in a
sealed container, as described above, which minimizes or prevents
leakage of ambient moisture into the container or a hopper drier
with a slight positive pressure when compared to the outside
environment. The adjustment of the moisture content of the drying
gas stream may be based on the moisture content of the drying
stream before passing through the polymer resin, after passing
through the polymer resin, or both.
[0063] The specified tolerance refers to a specified permissible
deviation from a target value above, below, or both above and below
the target value. The specified tolerance from the target value of
the polymer resin moisture content may be less than 1 ppm, 1 to 2
ppm, 2 to 3 ppm, 2 to 5 ppm, 5 to 10 ppm, 10 to 15 ppm, 10 to 20
ppm, 15 to 20 ppm, 20 to 30 ppm, 30 to 50 ppm, 50 to 100 ppm 100 to
200 ppm, or greater than 200 ppm.
[0064] In some embodiments, the adjustment of the moisture content
of the drying gas may include increasing or decreasing the moisture
content of the drying gas stream in order to maintain the polymer
resin moisture content within the selected range. Although the
temperature of the resin hopper or drying gas can be varied during
the process, the moisture content of the resin can be controlled
within the selected range without adjusting the temperature of the
drying process. The flow rate of the drying gas may be adjusted,
however, the moisture content of the resin can be controlled
without adjusting the flow rate of a dry gas stream that is free of
moisture. As described below, the flow rate adjustment of the
drying gas may be due to injection of a moist gas stream into a dry
gas stream.
[0065] A relationship between the moisture content of the polymer
resin in the sealed container and the moisture content of the
drying gas may be used to determine adjustments to the moisture
content of the drying gas that maintain the moisture content of the
polymer resin within the selected range. Specifically, a selected
range of moisture content of polymer resin may correspond to a
selected range of moisture content of drying gas. This relationship
depends on the temperature of the drying gas. Therefore, at a given
temperature, control of the moisture content of the drying gas
within the selected range will control the moisture content of the
polymer resin within a corresponding selected range. The moisture
content of the drying gas may be monitored, for example, in terms
of relative humidity and the corresponding moisture content of the
polymer resin may be in terms of ppm. The relative humidity of the
drying gas stream can be monitored instantaneously with inline
sensors that can provide instantaneous feedback for adjusting the
moisture content of the drying gas. Measurement of moisture content
of polymer resin separately does not allow for such feedback since
such measurements are performed offline and take several minutes to
perform.
[0066] The relationship between the moisture content of the polymer
resin in the sealed container and the moisture content of the
drying gas may be determined experimentally. For example, at a
selected temperature, the moisture content of a polymer resin as
function of the moisture content of the drying gas may be
determined. The corresponding ranges may be identified from such
data.
[0067] The method can include selecting a temperature of a drying
stream for maintaining the moisture content of the polymer resin in
the selected range or target value. The moisture content range or
target value of the drying stream is provided that corresponds to
the selected range or target value of polymer resin moisture
content at the selected temperature. The moisture content of the
drying gas may then be maintained in the selected range or target
value of the drying stream moisture content. The maintaining can
correspond to adjusting the moisture content of the drying stream
when the moisture content of the drying stream deviates from the
selected range or from the target value by a specified
tolerance.
[0068] For example, at a selected temperature, a target moisture
content of the resin corresponds to a target moisture content of
the drying gas. The measured moisture content of the drying gas is
compared to the target moisture content of drying gas. The moisture
content of the drying gas may then be adjusted to maintain the
drying gas moisture content within a specified tolerance of the
target moisture content.
[0069] The adjustments to the moisture content of the drying gas
can be based on the moisture content of the drying gas measured at
the entrance to the resin container. Alternatively, the adjustments
to the moisture content of the drying gas can be based on the
moisture content of the drying gas measured after passing through
the resin at the exit of the resin container. Another preferred
method is to base adjustments to the moisture content of the drying
gas on both the moisture content at the exit and entrance of the
resin container, and the difference between the two moisture
contents. In this case, the target value for the moisture content
of the drying gas at the entrance and exit is the target moisture
content that corresponds to the target resin content. In addition,
the target difference between the drying gas moisture content at
the entrance and exit is zero since this represents and equilibrium
condition. Thus, the moisture content of the drying gas is adjusted
to maintain the moisture content at the exit and entrance to be
within a specified tolerance and to be within a specified tolerance
of the equilibrium condition.
[0070] In certain embodiments, the drying gas stream can include a
first gas stream and the moisture content can be varied by
injecting in a second gas stream having a higher moisture content
into the first gas stream. The moisture content of the drying gas
stream can be increased by increasing the injection flow rate of
the second gas stream into the first gas stream. In some
embodiments, the first gas stream can be a dry gas stream that is
free or substantially free of moisture, as described above. For
example, the first gas stream has a dew point less than -40 or -45
deg C.
[0071] FIG. 4 depicts a schematic representation of an exemplary
system 150 for controlling moisture content of a polymer resin
prior to and during extrusion with a drying gas having variable
moisture content. System 150 includes a resin hopper 152 that holds
resin that is fed to an extruder (not shown) as shown by an arrow
154.
[0072] A drying gas stream 158 enters hopper 152 and passes through
the resin in the hopper. The temperature and humidity of drying gas
158 is monitored prior to entering hopper 152 by temperature and
humidity sensors 160. A drying gas stream 162 exits hopper 152
after having passed through the resin. A moisture sensor 163
monitors the moisture (e.g., humidity) of drying gas stream 162. A
sensor 161 monitors the pressure of drying gas stream 158. Drying
gas stream 162 is directed to a drier unit 164, such as a desiccant
bed. An overpressure valve 165 releases excess pressure from the
system. The drier unit 164 removes moisture from drying gas stream
162 to generate a dry gas stream 168 that is free or substantially
free of moisture. Drying gas stream 158 is generated by injecting a
moist gas stream 170 into dry gas stream 168. The moisture content
of the drying gas stream 158 is varied by adjusting amount of moist
gas stream 170 that is combined with dry gas stream 168.
[0073] Moist gas stream 170 is generated by a humidity conditioning
unit 172. A gas stream 176 regulated by flow controller 178 is
supplied from a compressed gas source 174 to unit 172. The humidity
conditioning unit 172 can supply moist gas stream 170 that has a
constant moisture content at a selected value, such as a selected
relative humidity. The moisture content of drying gas stream 158 is
adjusted by adjusting the flow rate of moist gas stream 170. This
adjustment may be performed by varying the flow rate of gas stream
176 to humidity conditioning unit 172 with flow rate controller
178. The adjustment of the moisture content of drying gas stream
158 through adjustment of the flow rate of gas stream 176 is based
on relative humidity (RH) measurements of drying gas stream 158 at
the entrance and exit of hopper 152. RHentr and RHexit are compared
to a target RH and ABS(RHentr-RHexit) is compared to the target
value of zero. Adjustments are made to the flow rate so that these
quantities are within a specified tolerance of the target
values.
[0074] The humidity conditioning unit may be obtained from
Parameter Generation & Control of Black Mountain, N.C. The 9310
series 100 CFM Conditioning Unit, for example, can generate an air
stream with selected temperature and humidity. When blended with
the dry air from the Dri-Air desiccant dryer, an gas stream with
any temperature and humidity can be produced. Even though the
Dri-Air system is a closed loop system, when humidified gas is
injected into the loop, the pressure can be managed. The hopper is
not completely air-tight and a vent valve in the loop can be
cracked open to prevent excess loop pressure. Other inert carrier
gases such as nitrogen could also be used.
[0075] In some embodiments, at the start of the drying process
prior to extrusion, the target value of the RH of the drying gas
could be set to a very low value to dry the resin very quickly.
This target RH may be below the target value of RH that corresponds
to the target polymer resin moisture content for extrusion. The
drying gas dew point then may be initially set to, for example, -40
deg C. In this initial phase, the flow rate of moist gas stream 170
may be set to zero. However, before extrusion begins, the moisture
content in the drying gas stream would be increased, by increasing
the target RH, to provide an equilibrium moisture content of the
resin a selected range, for example, 50 to 1000 ppm.
[0076] During this initial phase, the drying gas could be at an
elevated temperature such as 60 to 70 deg C., however, the
temperature could be lower, such as 25 to 30 deg C. In general, the
drying gas temperature can be between 25 deg C. and 70 deg C. An
advantage to keeping the temperature of the drying gas high in this
initial phase is that the resin will come to an equilibrium
moisture level more quickly. As long as the drying gas with a
controlled and low level of moisture is fed into the hopper, the
resin will remain at a fixed water content. In the second phase of
the drying process prior to and during extrusion when the moisture
content of the drying gas and polymer are controlled to be the
target, the drying temperature may be 25 to 70 deg C., or more
narrowly, 25 to 30, 30 to 40, 40 to 50, 50 to 60, or 60 to 70 deg
C. In exemplary embodiments, the drying gas temperature is 60 to 70
deg C. in the initial phase and the temperature of the drying gas
is 25 to 40 deg C. in the second phase.
[0077] In other embodiments, a shutoff one way valve may be
positioned between the drier unit and a source of pre-conditioned
gas (e.g., tank of nitrogen, compressed air) with a fixed moisture
content for injecting into a dry gas stream from the drier unit.
The hopper/dryer which holds the resin may be fitted with two
humidity sensors, one at the bottom of the hopper, just above the
gas/air inlet source and the other at the top of the hopper/dryer.
FIG. 5 depicts a schematic representation of another exemplary
system 200 for controlling moisture content of a polymer resin
prior to and during extrusion with a drying gas having variable
moisture content. System 200 includes a resin hopper 202 that holds
resin that is fed to an extruder 204.
[0078] A drying gas stream 206 with a variable moisture content
enters hopper 202 and passes through the resin in the hopper, the
direction of flow shown by an arrow 205. Hopper 202 has a humidity
sensor 208 at the bottom of the hopper and a humidity sensor 210 at
the top of the hopper for measuring the humidity at the exit and
entrance of the hopper, respectively. A drying gas stream 212 exits
hopper 202 and is directed to a drier unit 214 to generate a dry
gas stream 213. Drier unit 214 removes moisture from drying gas
stream 212 to generate dry gas stream 213 that is free or
substantially free of moisture. A compressed air source 216 is used
as a gas source for drier unit 214. Drying gas stream 206 with a
selected moisture content is generated by injecting a moist gas
stream 218 into dry gas stream 213.
[0079] The moisture content of the drying gas stream 206 is varied
by adjusting amount of moist gas stream 218 that is injected into
dry gas stream 213. The source of the moist gas stream 218 is a
preconditioned gas tank 220 containing a gas (e.g., nitrogen or
air) having a selected, constant moisture content which can be
between 50 and 10,000 ppm. A shutoff one way valve 222 is
positioned between drier unit 214 and preconditioned gas tank 220.
Valve 222 controls the injection of moist gas stream 218 injected
into dry gas stream 213, and therefore, the moisture content of
drying gas 206. The measurements from humidity sensors 208 and 210
are used as feedback to valve 222 to adjust the moisture content of
the drying gas 206 so that the resin is controlled to be within a
specified tolerance of the target moisture content. The system is
at a state of equilibrium when sensors 208 and 210 measure the same
moisture content.
[0080] Another embodiment similar to that depicted in FIG. 4 is
feeding a moist gas stream into the hopper having a constant
relative humidity. The moist gas stream may be air or nitrogen with
a moisture content of 50 and 2000 ppm. A slight positive pressure
may be maintained in the hopper, for example, between 15 and 20
psi. Additionally, the temperature of the drying gas and in the
hopper may be slightly elevated above ambient temperature, for
example, the temperature may be between 20 and 40 deg C., or more
narrowly between 30 and 35 deg C. Previous experiments by inventors
have shown that PLLA water equilibration is surprisingly very rapid
even at room temperature. Therefore, the resin is expected to
respond quickly to the moist gas environment. The system is
expected to reach equilibrium in less than 2 hours. Equilibrium
will be demonstrated by the inlet gas moisture content equal to the
outlet moisture content. Such a method would ensure that the resin
would always have a constant moisture content as it is charged into
the extruder.
[0081] Further embodiments of the present invention can include
plasticization of a polymer resin for feeding into an extruder with
substances other than moisture or water. In certain embodiments,
carbon dioxide may be used to plasticize a polymer resin. In some
embodiments, a gas containing carbon dioxide is passed through a
polymer resin in a hopper. The gas may be 100% carbon dioxide and
may be in a gas, liquid, or supercritical state. The gas may be a
blend of carbon dioxide and another gas such as air, nitrogen or
water.
[0082] The polymer resin absorbs the carbon dioxide and the carbon
dioxide flow through the resin may be continued until it is
saturated with carbon dioxide. The flow of carbon dioxide may be
continued during the extrusion process. As disclosed above, the
hopper may be sealed or have a positive pressure to minimize
exposure of the resin to ambient moisture.
[0083] The carbon dioxide permeates into the resin and acts as a
plasticizer during extrusion by reducing melt viscosity of the
resin. Unlike moisture, carbon dioxide is inert to PLLA and has
been used as a solvent to synthesize PLLA, and thus, will not cause
chemical degradation of PLLA resin. Voda, S. et al. Polymer 45
(2004) 7839-7843. The plasticization by the carbon dioxide is
expected to decrease the melt viscosity of the polymer resin in the
extruder, allowing lower extrusion temperatures with reduced
monomer generation and thermal degradation. Extrapolating published
data on the solubility of carbon dioxide in PLLA to one atmosphere
pressure, the solubility of CO2 in PLLA at 25 deg C. is on the
order of 0.5% or 5,000 ppm. Liao, X. et al. Polymer Int 2010; 59:
1709-1718.
[0084] The temperature of the gas may be 25 to 70 deg C., or more
narrowly, 25 to 30, 30 to 40, 40 to 50, 50 to 60, or 60 to 70 deg
C. The carbon dioxide content of the resin entering the extruder
can be 500 to 10,000 ppm, 500 to 5000 ppm, 1000 to 2000 ppm, 2000
to 3000 ppm, 3000 to 4000 ppm, or 4000 to 5000 ppm.
[0085] In some embodiments, the gas may be dry or have a low
moisture content. For example, the moisture content may be less
than 1500 ppm. The dry gas stream passing through the resin can
remove moisture from the resin to provide a low, consistent level
of moisture in the polymer resin. The target moisture content of
the resin may be less than 20 ppm, 20 to 50 ppm, 50 to 100 ppm, 100
to 300 ppm, 300 to 1000 ppm, or 50 to 1000 ppm. With regard to melt
viscosity, a low level of moisture is not a problem since the
carbon dioxide provides plasticization.
[0086] In some embodiments, rather than blending moist gas with a
dry air stream, as described above and illustrate in FIGS. 5 and 6,
carbon dioxide may be blended with a dry gas stream such as dry air
or nitrogen. The relative volume percent of carbon dioxide may be
1% to 99%, or more narrowly, 1 to 10%, 10 to 50%, 50 to 80%, or 80
to 90%.
[0087] In certain embodiments, freon may be used to plasticize a
polymer resin. In some embodiments, a gas containing freon may be
added to or passed through the hopper containing the resin. The
freon may be circulated through the hopper in a closed circulation
loop. The polymer resin may absorb some of the freon. The flow of
gas through the resin may be continued until it is saturated with
the freon. The flow of the gas may be continued during the
extrusion process.
[0088] In some embodiments, as described above for carbon dioxide,
the gas may be dry or have a low moisture content. The target
moisture content of the resin may be the same levels as described
above for carbon dioxide since the freon plasticizes the resin.
[0089] The choice of type of freon for use as a plasticizer for the
polymer resin may be dictated by several factors. These include
that the freon be a solvent for the polymer resin and plasticizes
the polymer resin melt. Additionally, the freon should be easily
removed from an extruded product. Therefore, the freon should have
a high vapor pressure of 300 torr or greater at 25 deg C., and be
either a gas or a low boiling liquid under ambient conditions,
i.e., 25 to 30 deg C. Consequently, the plasticizing agent will
evaporate and be easy to remove from an extruded product. The rate
of removal can be increased by heating the extruded product after
extrusion. Additionally, the freon should be non-toxic and
non-flammable. Table 1 is a list of freon plasticizers that are
expected to be useful for extrusion of PLLA.
TABLE-US-00001 TABLE 1 Potential Freons for Plasticizing PLLA.
Boiling Solubility Point Parameter Compound (C.) Toxicity
Flammability (cal/cm).sup.1/2 Fluoroform (CHF.sub.3), -82 Non-
Non-flammable na Freon 23 toxic 1,1,2,2-tetrafluoroethane, -26 Non-
Non-flammable na HFC-134a toxic 2,2-dichloro-1,1,1-tri- 28 Non-
Non-flammable na fluoroethane toxic HCFC-123 1,1,1,2,3,3,3-Hepta-
-16 Non- Non-flammable na fluoropropane toxic HFC-227ea Chloroform
61 Toxic Non-flammable 9.3 (p)
[0090] For the purposes of the present invention, the following
terms and definitions apply:
[0091] "Relative humidity" is a measurement of the amount of water
vapor in a mixture of air and water vapor. It is most commonly
defined as the partial pressure of water vapor in the air-water
mixture, given as a percentage of the saturated vapor pressure
under those conditions.
[0092] The "dew point" is the temperature to which a given parcel
of humid air must be cooled, at constant barometric pressure, for
water vapor to condense into water. The condensed water is called
dew. The dew point is a saturation temperature. The dew point is
associated with relative humidity. A high relative humidity
indicates that the dew point is closer to the current air
temperature. Relative humidity of 100% indicates the dew point is
equal to the current temperature and the air is maximally saturated
with water. When the dew point remains constant and temperature
increases, relative humidity will decrease.
[0093] The term "molecular weight" can refer to one or more
definitions of molecular weight. "Molecular weight" can refer to
the molecular weight of individual segments, blocks, or polymer
chains. "Molecular weight" can also refer to weight average
molecular weight or number average molecular weight of types of
segments, blocks, or polymer chains. The number average molecular
weight (Mn) is the common, mean, average of the molecular weights
of the individual segments, blocks, or polymer chains. Molecular
weight is typical expressed in grams/mole which is referred to as
"Daltons." It is determined by measuring the molecular weight of N
polymer molecules, summing the weights, and dividing by N:
M _ n = i N i M i i N i ##EQU00001##
where Ni is the number of polymer molecules with molecular weight
Mi. The weight average molecular weight is given by
M _ w = i N i M i 2 i N i M i ##EQU00002##
where Ni is the number of molecules of molecular weight Mi Unless
otherwise specified, "molecular weight" will refer to number
average molecular weight (Mn).
[0094] "Semi-crystalline polymer" refers to a polymer that has or
can have regions of crystalline molecular structure and amorphous
regions. The crystalline regions may be referred to as crystallites
or spherulites which can be dispersed or embedded within amorphous
regions.
[0095] The "glass transition temperature," Tg, is the temperature
at which the amorphous domains of a polymer change from a brittle
vitreous state to a solid deformable or ductile state at
atmospheric pressure. In other words, the Tg corresponds to the
temperature where the onset of segmental motion in the chains of
the polymer occurs. When an amorphous or semi-crystalline polymer
is exposed to an increasing temperature, the coefficient of
expansion and the heat capacity of the polymer both increase as the
temperature is raised, indicating increased molecular motion. As
the temperature is increased, the heat capacity increases. The
increasing heat capacity corresponds to an increase in heat
dissipation through movement. Tg of a given polymer can be
dependent on the heating rate and can be influenced by the thermal
history of the polymer as well as its degree of crystallinity.
Furthermore, the chemical structure of the polymer heavily
influences the glass transition by affecting mobility.
[0096] The Tg can be determined as the approximate midpoint of a
temperature range over which the glass transition takes place.
[ASTM D883-90]. The most frequently used definition of Tg uses the
energy release on heating in differential scanning calorimetry
(DSC). As used herein, the Tg refers to a glass transition
temperature as measured by differential scanning calorimetry (DSC)
at a 20.degree. C./min heating rate.
[0097] "Stress" refers to force per unit area, as in the force
acting through a small area within a plane. Stress can be divided
into components, normal and parallel to the plane, called normal
stress and shear stress, respectively. Tensile stress, for example,
is a normal component of stress applied that leads to expansion
(increase in length). In addition, compressive stress is a normal
component of stress applied to materials resulting in their
compaction (decrease in length). Stress may result in deformation
of a material, which refers to a change in length. "Expansion" or
"compression" may be defined as the increase or decrease in length
of a sample of material when the sample is subjected to stress.
[0098] "Strain" refers to the amount of expansion or compression
that occurs in a material at a given stress or load. Strain may be
expressed as a fraction or percentage of the original length, i.e.,
the change in length divided by the original length. Strain,
therefore, is positive for expansion and negative for
compression.
[0099] "Strength" refers to the maximum stress along an axis which
a material will withstand prior to fracture. The ultimate strength
is calculated from the maximum load applied during the test divided
by the original cross-sectional area.
[0100] "Modulus" may be defined as the ratio of a component of
stress or force per unit area applied to a material divided by the
strain along an axis of applied force that results from the applied
force. The modulus typically is the initial slope of a
stress-strain curve at low strain in the linear region. For
example, a material has both a tensile and a compressive
modulus.
[0101] The tensile stress on a material may be increased until it
reaches a "tensile strength" which refers to the maximum tensile
stress which a material will withstand prior to fracture. The
ultimate tensile strength is calculated from the maximum load
applied during a test divided by the original cross-sectional area.
Similarly, "compressive strength" is the capacity of a material to
withstand axially directed pushing forces. When the limit of
compressive strength is reached, a material is crushed.
[0102] "Toughness" is the amount of energy absorbed prior to
fracture, or equivalently, the amount of work required to fracture
a material. One measure of toughness is the area under a
stress-strain curve from zero strain to the strain at fracture. The
units of toughness in this case are in energy per unit volume of
material. See, e.g., L. H. Van Vlack, "Elements of Materials
Science and Engineering," pp. 270-271, Addison-Wesley (Reading,
Pa., 1989).
[0103] While particular embodiments of the present invention have
been shown and described, it will be obvious to those skilled in
the art that changes and modifications can be made without
departing from this invention in its broader aspects. Therefore,
the appended claims are to encompass within their scope all such
changes and modifications as fall within the true spirit and scope
of this invention.
* * * * *